The long-range objectives of this laboratory are to develop an understanding of the pathophysiology of diabetes mellitus in the hope that such knowledge permits the development of rational preventive and therapeutic measures. Such a goal is impossible without the clarification of normal physiology. Although the metabolic derangements in diabetes have traditionally focused upon net insulin deficiency (hypoinsulinemia in most experimental diabetes and hyperinsulinema in the diabetes associated with obesity), the emerging complexity of the islets of Langerhans, as a source of many peptide hormones (glucagon, somatostatin, endorphins, enkephalins, pancreatic polypeptides, TRH, gastrin, etc.) has shifted attention to the possible role of these hormones in the genesis of the diabetic state and its complications. Hyperglucagonemia and, more recently, hypersomatostatinemia have been noted to be present in experimental and spontaneous diabetes in animals and elevations of endorphins or enkephalins are postulated to be involved in obesity (often a pre-diabetic state) and noninsulin dependent human diabetes. In the present proposal we shall explore several broadly related questions dealing with these islet hormones and how these relate to the diabetic state in animals and human subjects. The role of specific receptors for insulin, glucagon, somatostatin and opiates in the control of islet cell secretion of these hormones will be studied. Fresh rat islets, and cultured "islets" as well as clones of alpha, beta and delta cells grown from islet cell tumors will be utilized. The nature and control of these receptors will be compared with peripheral tissue receptors as in circulating red blood cells and liver membranes.